Cryptococcus neoformans is a common cause of fatal fungal infection in patients with AIDS. The respiratory tract is the portal of entry for this ubiquitous, encapsulated yeast and the development of protective Th1 cell-mediated immunity (CMI) is crucial to eradicate the organism and control cryptococcal dissemination from the lungs to the brain. Production of cytokines and other mediators by cells of the innate immune system direct the development of CMI, but the precise nature of these early cellular and molecular events remains to be determined. CCR2 and other chemokine receptors (CKRs) have recently been identified as important co-factors for HIV infections and therapies aimed at blocking CKR binding are being considered. It is of considerable importance to understand the role of CKRs in host defense against infection by AIDS-associated pathogens because CKR antagonists will likely be used in patients concurrently infected with one or more of these pathogens. We have identified in preliminary studies with CCR2 knockout mice that protective Th1 immunity against C. neoformans cannot develop in the absence of CCR2 even if CD4+ and CD8+ T cell numbers in the lungs, blood, and spleen are normal. Hypothesis: MCP-1 via CCR2 mediates mononuclear cell co-stimulation and recruitment which is required to develop protective Th1 immunity against C. neoformans; deficient CCR2 function results in Th2 immunity and an inability to clear C. neoformans. Specific Aims: (1) To identify the cells in the lungs that express CCR2 during C. neoformans infection; (2) to determine the role of the CCR2 ligand MCP-1 in the development of Th1 immunity to C. neoformans; (3) to determine the role of CCR2 in the activation and recruitment of macrophages during pulmonary C. neoformans infection; (4) to determine the role of CCR2 in the recruitment and activation of T cells during pulmonary C. neoformans infection; (5) To determine the role of MCP-1 and CCR2 in the development of a Th2 response to C. neoformans.